Chlamydia pneumoniae (CP) is an important respiratory pathogen associated with community acquired pneumonia and bronchitis and significantly contributes to chronic debilitating pulmonary conditions such as bronchial asthma and COPD. However, the exact molecular mechanisms involved in CP-induced chronic lung inflammation and allergic airway inflammation are not clearly understood. While the protective effects of Th-17/IL-17 against certain microbial agents have been demonstrated, little is known about the role of Th17/IL-17 in host defenses against CP infection and their role in CP-induced chronic lung inflammation or allergic airway sensitization. Better understanding of the role of Th17IL-17 in the pathogenesis of COPD and allergic airway inflammation associated with CP infection may result in much needed new preventive and therapeutic approaches. During the last funding period we investigated the role of the innate immune receptors such as TLRs/MyD88 and NOD/RIP2 in host defenses against CP as well as their role in CP-induced allergic airway sensitization. We discovered that Rip2 signaling was critically required for efficient host defenses and bacterial clearance, and that Rip2-/- mice that survived initial infection developed a chronic lung inflammation. Importantly, we found that TH17 responses in Rip2-/- mice were significantly upregulated. A major goal of this project is to define the mechanism and cross talk between IL-17 production and lack of NOD/RIP2 signaling pathway in chronic lung inflammation during CP pulmonary infection. We also observed that allergic sensitization was dependent on infection severity with Tregs playing a critical role in determining the likelihood of sensitization, and that CP-induced IL-6 levels critically modulated Allergic Sensitization. Based upon these key findings, we now propose the following studies in this renewal application focused around the central hypothesis that TH17 cells promote chronic inflammation following CP infection, exacerbate asthmatic responses, and that lack of RIP2 signaling leads to increased IL-17 production, which in turn can induce severe chronic lung inflammation with granuloma-like lesions. Furthermore, IL-6 induced during the early stages of CP infection counteracts the suppressive effects of Tregs resulting in infection induced allergic sensitization. To define the mechanisms by which CP induced Th17/IL-17 responses lead to chronic lung inflammation, granuloma lesion, and to investigate the role of CP infection induced IL-6 in allergic airway sensitization, we propose the following three Specific Aims: Aim1 is to determine the role of IL-17 in host defenses in CP lung infection and allergic airway sensitization. Aim 2 is to determine the role of Rip2/IL-17 cross-talk in CP-induced chronic lung inflammation and allergic airway sensitization. Aim 3 is to determine the role of IL-6 in CP-induced allergic airway sensitization.